title: Fenretinide metabolism in humans and mice: utilizing pharmacological modulation of its metabolic pathway to increase systemic exposure.
abstract: OBJECTIVE
  High plasma levels of fenretinide [N-(4-hydroxyphenyl)retinamide (4-HPR)] were associated with improved outcome in a phase II clinical trial. Low bioavailability of 4-HPR has been limiting its therapeutic applications. This study characterized metabolism of 4-HPR in humans and mice, and to explore the effects of ketoconazole, an inhibitor of CYP3A4, as a modulator to increase 4-HPR plasma levels in mice and to increase the low bioavailability of 4-HPR.
  
  
  METHODS
  4-HPR metabolites were identified by mass spectrometric analysis and levels of 4-HPR and its metabolites [N-(4-methoxyphenyl)retinamide (4-MPR) and 4-oxo-N-(4-hydroxyphenyl)retinamide (4-oxo-4-HPR)] were quantified by high-performance liquid chromatography (HPLC). Kinetic analysis of enzyme activities and the effects of enzyme inhibitors were performed in pooled human and pooled mouse liver microsomes, and in human cytochrome P450 (CYP) 3A4 isoenzyme microsomes. In vivo metabolism of 4-HPR was inhibited in mice.
  
  
  RESULTS
  Six 4-HPR metabolites were identified in the plasma of patients and mice. 4-HPR was oxidized to 4-oxo-4-HPR, at least in part via human CYP3A4. The CYP3A4 inhibitor ketoconazole significantly reduced 4-oxo-4-HPR formation in both human and mouse liver microsomes. In two strains of mice, co-administration of ketoconazole with 4-HPR in vivo significantly increased 4-HPR plasma concentrations by > twofold over 4-HPR alone and also increased 4-oxo-4-HPR levels.
  
  
  CONCLUSIONS
  Mice may serve as an in vivo model of human 4-HPR pharmacokinetics. In vivo data suggest that the co-administration of ketoconazole at normal clinical doses with 4-HPR may increase systemic exposure to 4-HPR in humans.
authors.affiliation: Cancer Center and Departments of Cell Biology & Biochemistry Pharmacology & Neuroscience Internal Medicine Pediatrics, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA.
authors.forename: Jason P
authors.initials: JP
authors.lastname: Cooper
authors.forename: Kyunghwa
authors.initials: K
authors.lastname: Hwang
authors.forename: Hardeep
authors.initials: H
authors.lastname: Singh
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
authors.forename: C Patrick
authors.initials: CP
authors.lastname: Reynolds
authors.forename: Robert W
authors.initials: RW
authors.lastname: Curley
authors.forename: Simon C
authors.initials: SC
authors.lastname: Williams
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Maurer
authors.forename: Min H
authors.initials: MH
authors.lastname: Kang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics*; D002460:Cell Line; D004347:Drug Interactions; D017313:Fenretinide / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics*; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D008862:Microsomes, Liver / Q000378:metabolism; D015394:Molecular Structure
chemical_list: D000970:Antineoplastic Agents; D017313:Fenretinide; D007654:Ketoconazole